Pharmaceutical composition containing dimethyl fumarate for administration at a low daily dose

ABSTRACT

The present invention relates to pharmaceutical compositions containing dimethyl fumarate (DMF). More specifically, the present invention relates to a pharmaceutical composition for oral use in treating psoriasis by administering a low daily dosage in the range of 375 mg±5% dimethyl fumarate, wherein the pharmaceutical formulation is in the form of an erosion matrix tablet.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions containingdimethyl fumarate (DMF). More specifically, the present inventionrelates to a pharmaceutical composition for oral use in treatingpsoriasis (including moderate to severe plaque psoriasis) byadministering a low daily dosage in the range of 375 mg±5% dimethylfumarate, wherein the pharmaceutical formulation is in the form of anerosion matrix tablet.

BACKGROUND OF THE INVENTION

Fumaric acid esters, i.e. dimethyl fumarate in combination with salts ofethylhydrogen fumarate have been used in the treatment of psoriasis formany years. The combination is marketed under the trade name Fumaderm®.It is in the form of enteric coated tablets for oral use.

Fumaderm® is available in two different dosage strengths (Fumaderm®intial and Fumaderm®):

Fumaderm ® inital Fumaderm ® Dimethyl fumarate 30 mg 120 mg Ethylhydrogen fumarate, 67 mg 87 mg  Ca-salt Ethylhydrogen fumarate,  5mg 5 mg Mg-salt Ethylhydrogen fumarate,  3 mg 3 mg Zn-salt

The two strengths are intended to be applied in an individually baseddose regimen starting with Fumaderm® initial in an escalating dose, andthen after e.g. three weeks of treatment switching to Fumaderm®.However, a high frequency of side effects causes some patientdiscontinuation early in treatment. It is contemplated that thegastrointestinal side effects and flushing can, at least partially, beexplained by the release properties of the prescription formulation,leading to high local drug concentration on the intestinal mucosa andsubsequent high plasma concentration of drug metabolite.

To reduce the side effects, EP-A-1 131 065, EP-A-1 059 920 and EP-A-1123 092 suggest the preparation of DMF and/or MMF containingmicrotablets.

Another approach to reduce unwanted side effects is the preparation ofcontrolled-release formulations as disclosed in WO 2006/037342 A2.

Furthermore, specific controlled-release formulations are disclosed inWO 2010/079222 A1. Such controlled-release formulations comprise one ormore fumaric acid esters in an erosion matrix tablet having an entericcoating that is thinner than enteric coatings usual in the art. Thepharmaceutical formulations disclosed in WO 2010/079222 show excellentpharmacokinetic parameters.

The DMF formulations and dosing regimens administered in clinical trialshave been associated with gastrointestinal (GI) side-effects, such asflushing, diarrhea, stomach ache, stomach pain, abdominal pain,abdominal cramps, nausea, flatulence, tenesmus, meteorism, an increasedfrequency of stools, a feeling of fullness, and/or upper abdominalcramps.

In view of the above, it is the object to be solved by the presentinvention to lower the daily dose of dimethyl fumarate in an effectiveoral formulation for use in the treatment of psoriasis (includingmoderate to severe plaque psoriasis).

DISCLOSURE OF THE INVENTION

It has been surprisingly found that the solution to solve the aboveobject is to use dimethyl fumarate as the sole active ingredient in anerosion matrix tablet at a dose of 375 mg±5% per day.

The erosion matrix formulation will enable the slow and controlledrelease of the active ingredient DMF within the enteric lumen. The slowrelease enables the exposure of the enteral immune system, even prior toabsorption into the systemic circulation and during the absorptionprocess, to the active principle for a prolonged period of time. Thislocal exposure induces immune modulation locally in addition to thesystemic pharmacological action. These locally modulated immune cellsmediate the systemic pharmacological action, in addition to possiblesystemic effects. By this slow and controlled release, the activity ofDMF on the cells in the local immune system is improved, making apharmacological activity of the drug at the unexpected low dose level of375 mg±5% per day possible.

More specifically, the present invention concerns the following aspects:

According to the first aspect, the present invention is directed to apharmaceutical composition for oral use in treating psoriasis, whereinsaid composition is in the form of an erosion matrix tablet comprising atablet core and one or more coating(s), wherein the tablet corecomprises

i) 10 to 80% by weight dimethyl fumarate as an active substance, and

ii) 1 to 50% by weight of one or more rate-controlling agents,

wherein at least one of the one or more coating(s) is an enteric coatingapplied at a level of 1.5 to 3.5% by weight of the core, and

wherein the dose of dimethyl fumarate to be administered is 375 mg±5%per day.

According to another preferred aspect of the present invention, thetablet core of the pharmaceutical composition according to the abovementioned aspects comprises

i) 30 to 60% by weight of dimethyl fumarate; and

ii) 3 to 40% by weight of one or more rate-controlling agents.

It is preferred that the rate-controlling agent is a water-solublepolymer. It is even more preferred that the rate-controlling agent is acellulose polymer or a cellulose derivative or a mixture thereof.

According to another preferred aspect of the present invention, therate-controlling agent is selected from the group comprisinghydroxypropyl cellulose, hydroxypropyl methyl cellulose (HMPC), methylcellulose, carboxymethyl cellulose and mixtures thereof. Mostpreferably, the rate-controlling agent is hydroxypropyl cellulose.

According to another preferred aspect of the present invention, thetablet core of the pharmaceutical composition according to any one ofthe above aspects comprises a binder. According to a preferredembodiment, said binder is lactose.

According to more specific embodiments of the present invention, thetablet core of the pharmaceutical composition according to any one ofthe above aspects comprises:

i) 35-55% by weight of dimethyl fumarate;

ii) 3-12% by weight of hydroxypropyl cellulose; and

iii) 40-60% by weight of lactose.

More preferably, said tablet core comprises:

i) 40-50% by weight of dimethyl fumarate;

ii) 3-12% by weight of hydroxypropyl cellulose; and

iii) 45-55% by weight of lactose.

It is even more preferred that said tablet core comprises:

i) 42-48% by weight of dimethyl fumarate;

ii) 3-10% by weight of hydroxypropyl cellulose; and

iii) 45-52% by weight of lactose.

In another aspect of the present invention, the amount of hydroxypropylcellulose is 3-6% by weight in the above defined tablet cores.

According to further preferred embodiments of the present invention,said tablet core of said pharmaceutical composition according to any oneof the above aspects further comprises 0.15-0.7% by weight of magnesiumstearate and, optionally, 0.05 to 0.25% by weight of silicon dioxide.

In one aspect of the present inventions, said pharmaceutical compositionis for administration once, twice or three times daily.

The pharmaceutical composition according to any one of the above aspectsis for use in the treatment of psoriasis (including moderate to severeplaque psoriasis).

Furthermore, the present invention relates to the following embodiments:

-   -   1. A pharmaceutical composition in the form of an erosion matrix        tablet comprising a tablet core and one or more coating(s),        wherein the tablet core comprises        -   i) 10 to 80% by weight dimethyl fumarate as an active            substance, and        -   ii) 1 to 50% by weight of one or more rate-controlling            agents,        -   wherein at least one of the one or more coating(s) is an            enteric coating applied at a level of 1.5-3.5% by weight of            the core, and        -   wherein the erosion matrix tablet comprises from 375 mg±5%            of dimethyl fumarate.    -   2. The pharmaceutical composition of item 1 above, wherein the        tablet core comprises        -   i) 30 to 60% by weight of dimethyl fumarate; and        -   ii) 3 to 40% by weight of one or more rate-controlling            agents.    -   3. The pharmaceutical composition of item 1 or 2, wherein the        rate-controlling agent is a water-soluble polymer.    -   4. The pharmaceutical composition of any one of items 1-3,        wherein the rate-controlling agent is a cellulose polymer or a        cellulose derivative or a mixture thereof.    -   5. The pharmaceutical composition of item 4, wherein the        rate-controlling agent is selected from the group comprising        hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC),        methyl cellulose, carboxymethyl cellulose and mixtures thereof.    -   6. The pharmaceutical composition of item 5, wherein the        rate-controlling agent is hydroxypropyl cellulose.    -   7. The pharmaceutical composition of any one of the preceding        items, wherein the tablet core further comprises a binder.    -   8. The pharmaceutical composition of item 7, wherein the binder        is lactose.    -   9. The pharmaceutical composition of any one of the preceding        items, wherein the tablet core comprises:        -   i) 35-55% by weight of dimethyl fumarate;        -   ii) 3-12% by weight of hydroxypropyl cellulose; and        -   iii) 40-60% by weight of lactose.    -   10. The pharmaceutical composition of item 9, wherein the tablet        core comprises:        -   i) 40-50% by weight of dimethyl fumarate;        -   ii) 3-12% by weight of hydroxypropyl cellulose; and        -   iii) 45-55% by weight of lactose.    -   11. The pharmaceutical composition of item 10, wherein the        tablet core comprises:        -   i) 42-48% by weight of dimethyl fumarate;        -   ii) 3-10% by weight of hydroxypropyl cellulose; and        -   iii) 45-52% by weight of lactose.    -   12. The pharmaceutical composition of any one of the preceding        items, wherein the tablet core comprises:        -   i) 35-55% by weight of dimethyl fumarate;        -   ii) 3-6% by weight of hydroxypropyl cellulose; and        -   iii) 40-60% by weight of lactose.    -   13. The pharmaceutical composition of item 12, wherein the        tablet core comprises:        -   i) 40-50% by weight of dimethyl fumarate;        -   ii) 3-6% by weight of hydroxypropyl cellulose; and        -   iii) 45-55% by weight of lactose.    -   14. The pharmaceutical composition of item 13, wherein the        tablet core comprises:        -   i) 42-48% by weight of dimethyl fumarate;        -   ii) 3-5.5% by weight of hydroxypropyl cellulose; and        -   iii) 45-52% by weight of lactose.    -   15. The pharmaceutical composition of any one of the preceding        items, wherein the tablet core further comprises 0.15-0.7% by        weight of magnesium stearate and, optionally, 0.05 to 0.25% by        weight of silicon dioxide.    -   16. The pharmaceutical composition of any one of the preceding        items, wherein the erosion matrix tablet comprises about 375 mg        of dimethyl fumarate.    -   17. The pharmaceutical composition of any one of the preceding        items, wherein the dimethylfumarate is in the form of a        crystalline powder.    -   18. A method of treating psoriasis in a subject in need thereof,        said method comprising administering to said subject a        pharmaceutical formulation in the form of an erosion matrix        tablet comprising a tablet core and one or more coating(s),        wherein the tablet core comprises        -   i) 10 to 80% by weight dimethyl fumarate as an active            substance, and        -   ii) 1 to 50% by weight of one or more rate-controlling            agents,        -   wherein at least one of the one or more coating(s) is an            enteric coating applied at a level of 1.5-3.5% by weight of            the core, and        -   wherein the dose of dimethyl fumarate to be administered is            from 375 mg±5% per day.    -   19. The method of item 18, wherein the tablet core comprises        -   i) 30 to 60% by weight of dimethyl fumarate; and        -   ii) 3 to 40% by weight of one or more rate-controlling            agents.    -   20. The method of item 18 or 19, wherein the rate-controlling        agent is a water-soluble polymer.    -   21. The method of any one of items 18-29, wherein the        rate-controlling agent is a cellulose polymer or a cellulose        derivative or a mixture thereof.    -   22. The method of item 21, wherein the rate-controlling agent is        selected from the group comprising hydroxypropyl cellulose,        hydroxypropyl methyl cellulose (HPMC), methyl cellulose,        carboxymethyl cellulose and mixtures thereof.    -   23. The method of item 22, wherein the rate-controlling agent is        hydroxypropyl cellulose.    -   24. The method of any one of items 18-23, wherein the tablet        core further comprises a binder.    -   25. The method of items 24, wherein the binder is lactose.    -   26. The pharmaceutical composition of any one of items 18-25,        wherein the tablet core comprises:        -   i) 35-55% by weight of dimethyl fumarate;        -   ii) 3-12% by weight of hydroxypropyl cellulose; and        -   iii) 40-60% by weight of lactose.    -   27. The pharmaceutical composition of item 26, wherein the        tablet core comprises:        -   i) 40-50% by weight of dimethyl fumarate;        -   ii) 3-12% by weight of hydroxypropyl cellulose; and        -   iii) 45-55% by weight of lactose.    -   28. The pharmaceutical composition of item 27, wherein the        tablet core comprises:        -   i) 42-48% by weight of dimethyl fumarate;        -   ii) 3-10% by weight of hydroxypropyl cellulose; and        -   iii) 45-52% by weight of lactose.    -   29. The method of any one of items 18-25, wherein the tablet        core comprises:        -   i) 35-55% by weight of dimethyl fumarate;        -   ii) 3-6% by weight of hydroxypropyl cellulose; and        -   iii) 40-60% by weight of lactose.    -   30. The method of item 29, wherein the tablet core comprises:        -   i) 40-50% by weight of dimethyl fumarate;        -   ii) 3-6% by weight of hydroxypropyl cellulose; and        -   iii) 45-55% by weight of lactose.    -   31. The method of item 30, wherein the tablet core comprises:        -   i) 42-48% by weight of dimethyl fumarate;        -   ii) 3-5.5% by weight of hydroxypropyl cellulose; and        -   iii) 45-52% by weight of lactose.    -   32. The method of any one of items 18-31, wherein the tablet        core further comprises 0.15-0.7% by weight of magnesium stearate        and, optionally, 0.05 to 0.25% by weight of silicon dioxide.    -   33. The method of any one of items 18-32, wherein the dose of        dimethyl fumarate to be administered is about 375 mg of dimethyl        fumarate per day.    -   34. The method of any one of items 18-27, wherein the        dimethylfumarate is in the form a crystalline powder.    -   35. The method of any one of items 18-34, wherein the        composition is administered once, twice or three times daily.    -   36. The method of item 35, wherein the erosion matrix tablet        comprises from 375 mg±5% of dimethyl fumarate, and the erosion        matrix tablet is administered once daily.    -   37. The method of item 36, wherein the erosion matrix tablet        comprises about 375 mg of dimethyl fumarate.    -   38. The method of item 18, wherein said method comprises        administering to the subject in need thereof the erosion matrix        tablet of item 1 above, wherein following oral administration        under fasting conditions of the erosion matrix tablet        monomethylfumarate appears in the plasma of the subject upon        hydrolysis of dimethylfumarate and the Cmax of the        monomethylfumarate in the plasma of the subject is between about        0.3 mg/L and about 2 mg/L.    -   39. The method of item 18, wherein said method comprises        administering to the subject in need thereof the erosion matrix        tablet of item 1, wherein following oral administration under        fasting conditions of the erosion matrix tablet        monomethylfumarate appears in the plasma of the subject upon        hydrolysis of dimethylfumarate and the Tmax of the        monomethylfumarate in the plasma of the subject is between about        1.5 h and about 4.5 h.    -   40. The method of item 18, wherein said method comprises        administering to the subject in need thereof the erosion matrix        tablet of item 1, wherein following oral administration under        fasting conditions of the erosion matrix tablet        monomethylfumarate appears in the plasma of the subject upon        hydrolysis of dimethylfumarate and the circulating plasma        concentration of the monomethylfumarate in the plasma of the        subject starts within the first hour after administration, has        at least 50% of the achieved Cmax over about 1 h to 4.5 h and        can be measured in total over the course of about 5 h to 8 h.    -   41. The method of item 40, wherein the subject in need thereof        has mild to moderate plaque psoriasis, moderate to severe plaque        psoriasis, or severe plaque psoriasis.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The pharmaceutical composition in the form of a matrix tablet accordingto the present application is a controlled-release formulation thatreleases the active ingredient, i.e. dimethyl fumarate, in a sustainedmanner. More specifically, the erosion matrix preferably results inrelease of the dimethyl fumarate—when subjected to an in vitrodissolution test carried out at 37° C. and a paddle speed of 100 rpmemploying 0.1 N hydrochloric acid as dissolution medium during the first2 hours of the test and then 0.05 M phosphate buffer pH 6.8 asdissolution medium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 10% w/w, preferably 0% w/w to about 5% w/w, more preferably 0% w/wto <2% w/w of the total amount of dimethyl fumarate contained in thepharmaceutical composition is released, and

within the first 2.5 hours after start of the test from about 2% w/w toabout 20% w/w of the total amount of the dimethyl fumarate contained inthe pharmaceutical composition is released, and

within the first 3.5 hours after start of the test from about 35% w/w toabout 65% of the total amount of dimethyl fumarate contained in thepharmaceutical composition is released, and

within the first 6 hours after start of the test >85% w/w of the totalamount of dimethyl fumarate contained in the pharmaceutical compositionis released.

In the present context the term “API”, which is an abbreviation for“active pharmaceutical ingredient” and the term “active substance” areused interchangeably and refers to dimethyl fumarate that is to bereleased from the pharmaceutical formulation according to the invention.

With respect to in vitro methods, well-established methods areavailable, especially methods described by official monographs like e.g.United States Pharmacopeia (USP) or the European Pharmacopoeia. A personskilled in the art will know which method to choose and how to selectthe specific conditions to carry out the in vitro test. For instance,the USP prescribes in vitro tests be carried out at 37+/−1.0 such as37+/−0.5 degrees Celsius/Centigrade. In one aspect, a suitabledissolution test is one, wherein the dissolution profile is determinedas described in the United States Pharmacopoeia at 37° C. using a paddledissolution apparatus at 100 rpm employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and thenfollowed by 0.05 M phosphate buffer pH 6.8 as dissolution medium for theremaining test period. A person skilled in the art will know how toadjust the conditions applied, e.g. temperature, pH, paddle speed,duration etc. In a further aspect, the in vitro dissolution testing iscarried out as follows: A USP apparatus II (paddles) with 1 litrevessels is used. Bath temperature is set to 37° C.±0.5° C. and paddlespeed to 100 rpm. One tablet is placed in one vessel containing 750 ml0.1N HCl (pH 1.2) over 2 h. After that the pH is changed to 6.8 byadding 220 ml-250 ml 0.2 M sodium phosphate buffer. 2.5 ml samples aretaken at least after 2 h, 2.5 h, 3.5 h and 6 h, immediately stored at2-8° C. and analyzed by HPLC for DMF. The HPLC parameters are set asfollows: Column: Phenomenex Luna C18, 50×4.6 mm, 3 μm; column oventemperature 30° C., mobile phase: Methanol: 20 mM phosphate buffer pH3.0 (35:65 V/V), inject volume: 5 μl, Flow rate: 0.8 ml/min, UV-Detectorwavelength: 210 nm, run time 5 min, DMF retention time 3.5 min.

The release in vivo may be tested by measuring the plasma concentrationat predetermined time periods and thereby obtaining a plasmaconcentration versus time profile for the dimethyl fumarate or, ifrelevant, a metabolite thereof. Furthermore, it is contemplated thatmetabolism already takes place within the gastro-intestinal tract orduring passage of the gastro-intestinal mucosa. Accordingly, whendimethyl fumarate is administered, the relevant component to search forin the plasma may be the monomethyl ester and not the dimethylester offumaric acid.

Other tests may also be used to determine or to give a measure of therelease of the active substance in vivo. Thus, animals (e.g. minipigs,dogs, monkeys etc.) may be used as a model. The animals receive thecompositions under investigation and after specified periods of time,blood samples are collected and the content of the active ingredient (ormetabolite thereof, if relevant) is determined in plasma or specificorgans or extracted from the intestinal contents.

Another test involves the use of a specific segment of an animal orhuman intestine. The segment is placed in a suitable apparatuscontaining two compartments (a donor and a receiver) separated by thesegment, and the composition under investigation is placed in a suitablemedium in one compartment (the donor compartment). The composition willrelease the active substance that subsequently is transported across theintestinal segment. Accordingly, at suitable time intervals, theconcentration of the active substance (or, if relevant, the metabolite)is measured in the receiver compartment.

A person skilled in the art will be able to adapt the above-mentionedmethod to the specific composition.

In the present context, the term “relative bioavailability” refers to acomparison of the amount of drug absorbed in vivo (expressed as areaunder the curve (AUC)) after administration of two differentformulations or reference product. In the present context, the amount ofdrug absorbed, expressed as AUC, can be detected in the form of theactual drug administered, or as a metabolite thereof. The relativebioavailability can be expressed as a percentage of a reference AUC,i.e. AUC %.

In the present context the term “variability” refers to the variabilityof PK parameters (e.g. C_(max) and AUC) after administration of apharmaceutical formulation or a reference formulation. The variabilitycan be expressed as the coefficient of variation (CV) for a PKparameter, i.e. the ratio of the standard deviation to the mean.Reference to PK parameter values herein, such as Cmax and Tmax, refersto mean values obtained from human clinical studies in either fed orfasted subjects.

In the present context the term “tolerability” refers to the potentialof a drug to be endured by subjects and/or patients. In one aspect,“tolerability” is determined as the potential of a drug to be endured bysubjects and/or patients in early stages of treatment, such as withinthe first three months of start of therapy, such as within the firstmonth of start of therapy, such as within the first two weeks of startof therapy, such as within the first week of start of therapy, such aswithin the first three days of start of therapy, such as within thefirst day of start of therapy, such as after the first dose of thetherapy. A drug with better tolerability produces fewer side effects ina subject and/or patient c.f. a drug with worse tolerability.

In the present context the term “substantial absence of” refers to alevel of less than about 1%, such as less than about 0.5%, such as lessthan about 0.3%, such as about 0.0%.

In the present context the terms “rate-controlling agent” and“rate-controlling agent in the form of a polymeric matrix material” areused interchangeably and refer to an agent that is able to sustainand/or prolong the in vivo and/or in vitro release of the activesubstance.

As mentioned above, the in vivo and/or in vitro release of the activesubstance is “controlled”, i.e. prolonged and/or slow compared with thecommercially available Fumaderm® composition. In the present context,the term “controlled” is intended to indicate that the active substanceis released during a longer time period than Fumaderm® such as at leastduring a time period that is at least 1.2 times, such as, e.g., at least1.5 times, at least 2 times, at least 3 times, at least 4 times or atleast 5 times greater than that of Fumaderm®. Thus, if e.g. 100% ofdimethyl fumarate is released from Fumaderm® tablets 3 hours after thestart of a suitable test, then 100% of dimethyl fumarate in acomposition according to the invention is released at least 3.6 hoursafter the start of a suitable test.

The formulation according to the invention is contemplated to provideimproved tolerability, such as fewer and/or less severe gastrointestinal(GI) side-effects, such as fewer and/or less severe redness episodes,such as fewer and/or less severe flushing episodes.

As used in the present invention, a gastrointestinal (GI) side effectmay include, but is not limited to diarrhea, emesis, stomach ache,stomach pain, abdominal pain, abdominal cramps, nausea, flatulence,tenesmus, meteorism, an increased frequency of stools, a feeling offullness and upper abdominal cramps.

In the present context, a reduction of GI related side effects isintended to denote a decrease in severity and/or incidence among a giventreated patient population, comparing the GI side effects observed afteradministration of the formulation according to the invention to the GIside effects observed after administration of Fumaderm®. A reduction inGI related side effects according to this definition could thus beconstrued as a substantial reduction in incidence of any of the GI sideeffect listed above, such as at least a 10% reduction in incidence ormore preferably at least 20% reduction in incidence or even morepreferable a more than 30% reduction in incidence. A reduction in GIrelated side effect can also be expressed as a substantial reduction inseverity in any of the GI side effects listed above, such as a reductionin severity and/or frequency of diarrhea, emesis, stomach ache, stomachpain, abdominal pain, abdominal cramps, nausea, flatulence, tenesmus,meteorism, increased frequency of stools, a feeling of fullness or upperabdominal cramps. The reduction of GI related side effects, as describedabove, can be monitored in a clinical trial setting, either comparingthe administration of the formulation according to the invention head onwith Fumaderm® or with placebo. In case of a placebo controlled trial,the incidence of GI related side effects in the patients receiving theformulation according to the invention compared to the placebo group,can be compared to historical trials comparing Fumaderm® to placebo (seee.g. Altmeyer et al, J. Am. Acad. Dermatol. 1994; full reference:Altmeyer P J et al., Antipsoriatic effect of fumaric acid derivatives.Results of a multicenter double-blind study in 100 patients. J. Am.Acad. Dermatol. 1994; 30:977-81).

In a further aspect, the formulation according to the invention—uponoral administration and in comparison to that obtained after oraladministration of Fumaderm® tablets in an equivalent dosage—reduce (GI)side-effects (frequency and/or severity).

WO 2010/079222 A1 discloses that an erosion matrix formulation upon oraladministration and in comparison to that obtained after oraladministration of Fumaderm® tablets in an equivalent dosage reducesunwanted side effects, in particular flushing (frequency and/orseverity). Frequency and strength of these and other side effects arefurther reduced in view of the low daily dosage of 375 mg±5%.

In the present context the term “flushing” describes episodic attacks ofredness of the skin together with a sensation of warmth or burning ofthe face and/or neck, and less frequently the upper trunk and abdomen orthe whole body. It is the transient nature of the attacks thatdistinguishes flushing from the persistent erythema of photosensitivityor acute contact reactions. Repeated flushing over a prolonged period oftime can lead to telangiectasia and occasionally to classical rosacea ofthe face (Greaves M W. Flushing and flushing syndromes, rosacea andperioral dermatitis. In: Champion R H, et al, eds. Rook/Wilkinson/Eblingtextbook of dermatology, 6th ed., vol. 3. Oxford, UK: BlackwellScientific, 1998: 2099-2104).

In the present context, a reduction of flushing is intended to denote adecrease in severity and/or incidence/frequency among a given treatedpatient population of flushing observed after administration of theformulation according to the invention compared with flushing observedafter administration of Fumaderm® and can be measured e.g. as describedby O'Toole et al. Cancer 2000, 88(4): p. 770-776. A reduction influshing according to this definition could thus be construed as areduction in incidence and/or severity of flushing. In one aspect of theinvention, the incidence of flushing is reduced by at least about aquarter, in another aspect of the invention the incidence is reduced byat least about a third, in another aspect of the invention the incidenceis reduced by at least about half, and in a further aspect of theinvention, the flushing incidence is reduced by about two thirds ormore. Likewise, the severity is in one aspect of the invention reducedby at least about a quarter, in another aspect of the invention by atleast about a third, in another aspect of the invention by at leasthalf, and in a further aspect of the invention by at least about twothirds. A one hundred percent reduction in flushing incidence andseverity is most preferable, but is not required. The reduction offlushing, as described above, can be monitored in a clinical trialsetting, e.g. comparing the administration of the compound according tothe invention with e.g. administration of Fumaderm®. In case of aFumaderm® controlled trial, the incidence and severity, defined as mild,moderate or severe, of flushing in the patients receiving the compoundaccording to the invention compared to the Fumaderm® group, can becompared.

In one aspect, the severity of flushing is determined as the bodysurface area involved. In one embodiment, such a clinical trial can becarried out as described above under “Clinical trial in patients”. Inanother embodiment, such a clinical trial can be carried out asdescribed above under “Clinical trial in healthy volunteers”.

In a further aspect, the formulation according to the invention—uponoral administration and in comparison to that obtained after oraladministration of Fumaderm® tablets in an equivalent dosage—reduceredness (frequency and/or severity).

In the present context the term “redness” describes episodic attacks ofredness of the skin. In one aspect, the redness occurs in the face,neck, and less frequently the upper trunk and abdomen.

In the present context, a reduction of redness is intended to denote adecrease in severity and/or incidence/frequency among a given treatedpatient population of redness observed after administration of theformulation according to the invention compared with redness observedafter administration of Fumaderm® and can e.g. be assessed by aclinician or nurse.

A reduction in redness according to this definition could thus beconstrued as a reduction in incidence and/or severity of redness. In oneaspect of the invention, the incidence of redness is reduced by at leastabout a quarter, in another aspect of the invention the incidence isreduced by at least about a third, in another aspect of the inventionthe incidence is reduced by at least about half, and in a further aspectof the invention, the redness incidence is reduced by about two thirdsor more. Likewise, the severity is in one aspect of the inventionreduced by at least about a quarter, in another aspect of the inventionby at least about a third, in another aspect of the invention by atleast half, and in a further aspect of the invention by at least abouttwo thirds. A one hundred percent reduction in redness incidence andseverity is most preferable, but is not required. The reduction ofredness, as described above, can be monitored in a clinical trialsetting, e.g. comparing the administration of the compound according tothe invention with e.g. administration of Fumaderm®. In case of aFumaderm® controlled trial, the incidence and severity, defined as mild,moderate or severe, of redness in the patients receiving the compoundaccording to the invention compared to the Fumaderm® group, can becompared.

In one aspect, the severity of redness is determined as the body surfacearea involved.

In one embodiment, such a clinical trial can be carried out as describedabove under “Clinical trial in patients”.

In another embodiment, such a clinical trial can be carried out asdescribed above under “Clinical trial in healthy volunteers”.

In one embodiment, the relative bioavailability of the formulation ofthe invention compared to Fumaderm® is at least about 75%, such as atleast about 80%, such as at least about 85%, such as at least about 90%,such as at least about 95%, such as about 100%.

In the present context the term “erosion matrix” refers to a matrixwherein the release of the API does not depend upon intrinsic diffusionprocesses but rather is the result of the rate of the matrix erosion. Bystripping off the erodible matrix layers in a well-controlled manner,predetermined amounts of the API will be obtained, with the release ofAPI being dependent on the rate of swelling and dissolution or erosionof the matrix and on the rate of dissolution, solubility and rate ofdiffusion of the API.

In an aspect of the invention, the rate-controlling agent is awater-soluble polymer. As used herein, the term “water-soluble polymer”means a conventional polymer for pharmaceutical use, having a solubilityof more than 10 mg/ml in water. Suitable water-soluble polymersincludes, but are not limited too, for example, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethylcellulose. According to a preferred embodiment, the water-solublepolymer is hydroxypropyl cellulose.

As used herein, the term “water-insoluble polymer” means a conventionalpolymer for pharmaceutical use, having a solubility of not more than 10mg/ml in water.

In a further aspect of the invention, the erosion matrix containsessentially no water-insoluble polymer. In yet a further aspect, theerosion matrix contains no water-insoluble polymer.

In the present context the term “essentially no” refers to a level ofless than about 1%, such as less than about 0.5%, such as less thanabout 0.3%, such as about 0.0%.

In an aspect of the invention, the rate-controlling agent is awater-soluble polymer and the erosion matrix contains essentially nowater-insoluble polymer.

According to a preferred aspect of the invention, the rate-controllingagent is a water-soluble polymer and the erosion matrix contains nowater-insoluble polymer.

In an embodiment of the invention, the rate-controlling agent is acellulose polymer or a cellulose derivative or a mixture thereof. Asnon-limiting examples of a cellulose polymer or a cellulose derivativeor a mixture thereof may be mentioned hydroxypropyl cellulose,hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethylcellulose and mixtures thereof.

According to the most preferred embodiment of the present invention, therate-controlling agent is hydroxypropyl cellulose.

Many different grades of hydroxypropyl cellulose exist depending on e.g.the molecular weight thereof, the degree of etherification, viscosityetc. Non-limiting exemplary embodiments of commercially availablehydroxypropyl celluloses are obtainable from e.g. 5 Aqualon or NipponSoda under the trade names Klucel® HPC-L, HPC-SL, HPC-SSL, HPC-M, HPC-Hetc. In an embodiment of the invention, the rate-controlling agent ishydroxypropyl cellulose having a viscosity (mPa·s) of 3.0-5.9 asmeasured in an aqueous solution containing 2% by weight of dry HPC at20° C. In an embodiment of the invention, the rate-controlling agent isHPC-SL.

According to the present invention, the rate-controlling agent ispresent in an amount of 1-50% by weight, 1-40% by weight, such as 3-35%by weight, such as 4-15% by weight, such as 4-10% by weight, such as3-15% by weight, such as 3-12% by weight, such as 3-10% by weight, suchas 3-6% by weight, such as 3-5.5% by weight, and such as 4-6% by weight.

In an aspect, the present invention relates to a pharmaceuticalformulation comprising an erosion matrix which comprises:

-   -   i) 10% to 80%, such as 20% to 70%, such as 20% to 60%, such as        30% to 60%, such as 35% to 60%, such as 35% to 55%, such as 40%        to 55%, such as 40% to 50%, such as 44% to 55%, such as 42% to        48%, by weight of dimethyl fumarate as an active substance; and    -   ii) 1% to 50%, such as 1% to 40%, such as 3% to 40%, such as 3%        to 20% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled release ofsaid active substance.

The amount of rate-controlling agent varies in accordance with thespecific rate-controlling agent used, the release profile aimed at, thelevel and nature of any excipients and additives present in the coretablet, etc.

According to a preferred embodiment of the invention, the pharmaceuticalcomposition further comprises a binder.

Non-limiting examples of a binder include water-soluble sugars and sugaralcohols, such as lactose, saccharose, glucose, sorbitol, mannitol etc.In a particularly preferred embodiment, said binder is lactose. Lactoseis commercially available in a number of different grades depending i.e.on the manufacturing method used resulting in a range of particle sizes,particle size distributions etc. Examples of lactose include, but arenot limited to anhydrous lactose, lactose made fromalpha-lactose-monohydrate, agglomerated lactose, granulated lactose,crystalline lactose, crystalline, sieved lactose, sieved lactose (e.g.PrismaLac®, such as PrismaLac® 40), crystalline, abrasive lactose (e.g.GranuLac®, such as GranuLac® 70, GranuLac® 140, GranuLac® 200, GranuLac®230 and GranuLac® 400), improved lactose, agglomerated lactose (e.g.Tablettose®, such as Tablettose® 70, Tablettose® 80 and Tablettose®100), improved lactose, spraydried lactose (FlowLac®, such as FlowLac®90 and FlowLac® 100). Lactose is available from e.g. Meggle Pharma underthe trade names PrismaLac®, Capsulac®, such as Capsulac®60, SacheLac®,SpheroLac®, Inhalac® GranuLac®, such as GranuLac® 70, GranuLac® 140,GranuLac® 200, GranuLac® 230 and GranuLac® 400, SorboLac®, Tablettose®,such as Tablettose® 70, Tablettose® 80 and Tablettose® 100, 25 FlowLac®,such as FlowLac® 90 and FlowLac® 100.

In one aspect, the lactose is agglomerated lactose. In another aspect,the lactose is spraydried lactose. In another aspect, the lactose isabrasive lactose.

In an embodiment of the invention, the tablet core of the pharmaceuticalcomposition according to the invention comprises:

-   -   i) 40 to 60% by weight of dimethyl fumarate as an active        substance; and    -   ii) 40 to 60% by weight, preferably, 45 to 55% by weight, of a        binder, preferably lactose.

According to a preferred embodiment of the present invention, the tabletcore of the pharmaceutical composition according to the presentinvention comprises:

-   -   i) 35% to 55% by weight dimethyl fumarate as an active        substance;    -   ii) 3 to 12% by weight of a rate-controlling agent;    -   iii) 40 to 60% by weight of a binder.

Even more preferred is an embodiment, wherein the tablet core of thepharmaceutical composition of the present invention comprises:

-   -   i) 40 to 50% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 12% by weight of hydroxypropyl cellulose, in particular        3 to 6% by weight;    -   iii) 45 to 55% by weight of lactose.

In another preferred embodiment of the invention, the tablet core of thepharmaceutical composition according to the present invention comprises:

-   -   i) 42% to 48% by weight of dimethyl fumarate;    -   ii) 3 to 10% by weight of hydroxypropyl cellulose, in particular        3 to 6% by weight;    -   iii) 45-52% by weight of lactose.

In an embodiment the composition according to the invention furthercomprises one or more lubricants.

In a preferred embodiment the pharmaceutical composition according tothe invention further comprises one or more lubricant(s) and/or one ormore flow control agent(s).

More specifically, in an embodiment of the invention, the tablet core ofthe pharmaceutical composition according to the present inventioncomprises:

-   -   i) 35 to 55% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 12% by weight of rate-controlling agent, such as        hydroxylpropyl cellulose;    -   iii) 40 to 60% by weight of binder, such as lactose;    -   iv) 0.15 and 0.7% by weight of lubricant, such as magnesium        stearate;

and optionally 0.05-0.25% by weight of flow control agents, such assilicon dioxide.

In an even more preferred embodiment of the invention, the tablet coreof the pharmaceutical composition according to the invention comprises:

-   -   i) 40 to 50% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 12% by weight of rate-controlling agent, such as        hydroxylpropyl cellulose;    -   iii) 45 to 55% by weight of binder, such as lactose;    -   iv) 0.15-0.7% by weight of lubricant, such as magnesium        stearate;

and optionally 0.05-0.25% by weight of flow control agents, such assilicon dioxide.

In an even more preferred embodiment of the invention, the tablet coreof the pharmaceutical composition according to the invention comprises:

-   -   i) 42 to 48% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 10% by weight of rate-controlling agent, such as        hydroxylpropyl cellulose;    -   v) 45 to 52% by weight of binder, such as lactose;    -   vi) 0.15-0.7% by weight of lubricant, such as magnesium        stearate;

and optionally 0.05-0.25% by weight of flow control agents, such assilicon dioxide.

In another preferred embodiment of the invention, the tablet core of thepharmaceutical composition according to the invention comprises:

-   -   i) 35 to 55% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 6% by weight of rate-controlling agent, such as        hydroxypropyl cellulose;    -   iii) 40-60% by weight of binder, such as lactose;    -   iv) 0.2-0.5% by weight of lubricant, such as magnesium stearate;    -   v) and optionally 0.05-0.2% by weight of flow control agents,        such as silicon dioxide.

In another even more preferred embodiment of the invention, the tabletcore of the pharmaceutical composition according to the inventioncomprises:

-   -   i) 35 to 55% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 6% by weight of rate-controlling agent, such as        hydroxypropyl cellulose;    -   iii) 45-55% by weight of binder, such as lactose;    -   iv) 0.2-0.5% by weight of lubricant, such as magnesium stearate;    -   v) and optionally 0.05-0.2% by weight of flow control agents,        such as silicon dioxide.

In the most preferred embodiment of the invention, the tablet core ofthe pharmaceutical composition according to the invention comprises:

-   -   i) 35 to 55% by weight of dimethyl fumarate as an active        substance;    -   ii) 3 to 5.5% by weight of rate-controlling agent, such as        hydroxylpropyl cellulose;    -   iii) 45 to 52% by weight of binder, such as lactose;    -   iv) 0.2-0.5% by weight of lubricant, such as magnesium stearate;    -   v) and optionally 0.05-0.2% by weight of flow control agents,        such as silicon dioxide.

According to the present invention, any pharmaceutically acceptablelubricant common in the art may be used in the pharmaceuticalcomposition of the present invention. Magnesium stearate may bepreferably used as a lubricant.

According to the present invention, any pharmaceutically acceptable flowcontrol agent common in the art may be used in the pharmaceuticalcomposition of the present invention. Silicon dioxide may be preferablyused as a flow control agent.

In an embodiment the formulation according to the invention may furthercomprise pharmaceutically acceptable excipients and additives selectedfrom the group comprising lubricants, glidants, disintegrants, flowcontrol agents, solubilizers, pH control agents, surfactants andemulsifiers. The amounts of such excipients and additives may beadjusted such that the properties of the pharmaceutical composition arenot deteriorated.

In an embodiment, the formulation according to the invention ismanufactured without the use of a disintegrant, i.e. it is preferredthat the pharmaceutical composition of the present invention does notcontain any disintegrant. However, small amounts of a disintegrant areallowed as long as the presence of the disintegrant does not causes theerosion matrix tablet to disintegrate.

According to the present invention, at least one of the one or morecoating(s) is an enteric coating.

Enteric coating materials may be selected from any of a number ofcommercially available 30 coating materials. Non-limiting examplesthereof include Eudragit® E, L, S, L30 D-55, Kollicoat® 30D, CelluloseAcetate Phthalate, Polyvinyl Acetate Phthalate, and HypromellosePhthalate. According to a preferred embodiment, the solution used ascoating solution for preparing the essential enteric coating comprisesEudragit® L30 D-55, triethyl citrate, glycerol monostearate, andPolysorbate 80.

According to the present invention, said essential enteric coating isapplied at a level of 1.5 to 3.5% by weight of the tablet core, such as2.0 to 3.5% by weight of the tablet core, such as 2 to 3% by weight ofthe tablet core. According to a particularly preferred embodiment, thecoating additionally fulfills the proviso that it is typically appliedto a level of about 2.0 mg/cm² to about 3.5 mg/cm² of the core tablet,such as about 2.5 mg/cm² to about 3.5 mg/cm² of the core tablet, such asabout 2.8 mg/cm² to about 3.3 mg/cm² of the core tablet.

Enteric coating is a well-established approach to prevent or minimisedrug release in the stomach and allow release in the small intestine.Such enteric polymer coatings work on the principle of pH dependentsolubility: insoluble in the low pH conditions of the stomach butsoluble in the near neutral pH environment of the proximal smallintestine having a pH in the range 5-6.

For drugs requiring absorption in the small intestine this leaves openonly a narrow window of release, such as about 6 h, such as about 5hours, such as about 4 hours, such as about 3 hours, hours betweendissolution of the enteric coating and release of the API from theformulation. It has been found that rapid dissolution of the entericcoating is possible by the application of a relatively thin coat, i.e.an amount of 1.5 to 3.5% by weight of enteric coating relative to thetablet core, while surprisingly still obtaining the required protectionagainst the acid environment of the stomach as e.g. shown—when subjectedto an in vitro dissolution test employing 0.1 N hydrochloric acid asdissolution medium during 2 hours-by less than 10%, such as less than5%, such as less than 2%, such as about 0% release of the fumaric estercontained in the formulation.

In an embodiment of the invention, the formulation according to theinvention comprises an enteric coating and the in vivo release of thedimethyl fumarate displays an earlier onset of release than the priorart formulation Fumaderm®, such as at least 20 minutes, at least 30minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes,at least 70 minutes, at least 80 minutes, at least 90 minutes, at least100 minutes, at least 110 minutes, or at least 120 minutes earlier thanFumaderm® under fasting conditions.

In an embodiment of the invention, the formulation according to theinvention comprises an enteric coating and the in vivo release of thedimethyl fumarate displays a lag time of 15 minutes to 2 hours underfasting conditions, such as a lag time of at the most 120 minutes, atthe most 110 minutes, at the most 100 minutes, at the most 90 minutes,at the most 80 minutes, at the most 70 minutes, at the most 60 minutes,at the most 50 minutes, at the most 40 minutes, at the most 30 minutes,at the most 20 minutes, or at the most 15 minutes under fastingconditions.

According to a preferred embodiment of the invention, the release of thedimethyl fumarate—when subjected to an in vitro dissolution testemploying 0.1 N hydrochloric acid as dissolution medium during the first2 hours of the test and then 0.05 M phosphate buffer pH 6.8 asdissolution medium is as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 10% w/w, preferably 0% w/w to about 5% w/w, more preferably 0% w/wto <2% w/w of the total amount of dimethyl fumarate contained in thepharmaceutical composition is released, and

within the first 2.5 hours after start of the test from about 2% w/w toabout 20% w/w of the total amount of the dimethyl fumarate contained inthe pharmaceutical composition is released, and

within the first 3.5 hours after start of the test from about 35% w/w toabout 65% of the total amount of dimethyl fumarate contained in thepharmaceutical composition is released, and

within the first 5 hours after start of the test >85% w/w of the totalamount of dimethyl fumarate contained in the pharmaceutical compositionis release.

In an embodiment the pharmaceutical composition according to theinvention is for administration once, twice or three times daily.

According to a preferred embodiment, the pharmaceutical composition isfor administration once daily. In such a case, the pharmaceuticalcomposition according to the present invention may preferably contain atotal amount of dimethyl fumarate as the active substance of 375 mg±5%,preferably about 375 mg.

According to another preferred embodiment according to the presentinvention, the pharmaceutical composition is for administration threetimes daily. In such a case the pharmaceutical composition preferablycontains a total amount of dimethyl fumarate of 125 mg.

The daily dosage of the controlled release pharmaceutical compositionaccording to the invention that is administered to treat a patientdepends on a number of factors among which are included, withoutlimitation, weight and age and the underlying causes of the condition ordisease to be treated, and is within the skill of a physician todetermine.

According to the present invention, the daily dosage of dimethylfumarate is 375 mg±5%, i.e. a range of 356.25 to 393.75 mg. The dailydosage may be given in, e.g. one to three doses.

Preparation of the erosion matrix tablets according to the invention maybe obtained by granulation, followed by tableting, enteric coating andoptionally film coating of the core tablets obtained. The core can forexample be made by conventional wet granulation or continuousgranulation such as extrusion followed by compaction of the granulesinto tablets. The core may then be coated using an appropriatetechnology, preferably by air suspension.

An aspect of the invention is a method for preparing the formulationaccording to the invention, comprising the steps of:

-   -   a) Dissolving (or suspending) either one or both of a fumaric        acid ester and optionally a rate-controlling agent in the form        of a polymeric matrix material in water to obtain an aqueous        suspension thereof;    -   b) Spraying said aqueous suspension on granules of a fumaric        acid ester and/or a binder for a period of time sufficient to        obtain a uniform coating thereon;    -   c) Drying the granules obtained;    -   d) Optionally sieving or milling said granules;    -   e) Blending of any pharmaceutically acceptable excipients and        additives in a manner known per se to obtain a tablet        formulation;    -   f) Enteric coating and optionally film coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C.

In an embodiment of the invention any of or all of the above steps areperformed at a temperature to allow a product temperature not exceeding40° C., such as not exceeding 35° C., such as not exceeding 30° C. Thusit has surprisingly been shown that the preparation of the formulationaccording to the invention may be obtained by the use of solely water assolvent, thus obviating the need for any organic solvents. Furthermoreall process steps may be carried out at a rather low temperature.Thereby any sublimation of the active pharmaceutical ingredient isminimised or reduced and an energy-efficient process is obtained,mitigating loss of API, thus reducing cost as well as improvingenvironmental and workers' safety.

In the present context particle size is measured by conventional sieveanalysis known to the person skilled in the art.

It is preferred that the mean particle size of the active pharmaceuticalingredient (the dimethyl fumarate) is reduced, e.g. by sieving ormilling, such that at least 50% of the particles have a particle size ofless than 800 μm, such as less than 600 μm, such as less than 500 μm,such as less than 400 μm, such as less than 300 μm, such as less than200 μm prior to step a) above.

In another preferred embodiment, the mean particle size of the activepharmaceutical ingredient (the dimethyl fumarate) is reduced, e.g. bysieving or milling, such that at least 80% of the particles have aparticle size of less than 800 μm, such as less than 600 μm, such asless than 500 μm, such as less than 400 μm, such as less than 200 μm,prior to step a) above.

According to a preferred embodiment, the mean particle size of thecrystalline active pharmaceutical ingredient dimethyl fumarate isreduced, e.g. by sieving or milling, such that at least 90% of theparticles have a particle size of less than 800 μm, such as less than600 μm, such as less than 500 μm, such as less than 400 μm, such as lessthan 200 μm, prior to step a) above.

In an embodiment of the invention the mean particle size of thecrystalline active pharmaceutical ingredient dimethyl fumarate may bereduced, e.g. by sieving or milling, wherein said sieving or milling isperformed producing a minimum amount of heat. Thereby any sublimation ofthe active pharmaceutical ingredient is minimised or reduced and anenergy-efficient process is obtained, mitigating loss of API, thusreducing cost as well as improving environmental and workers' safety.The sieving or milling may take place as a single sieving or millingstep or may optionally be repeated several times to obtain the requiredparticle distribution.

In one embodiment of the invention, the sieving or milling takes placeas a two-step process.

In one embodiment of the invention, where the sieving or milling isperformed as several steps an agent for reducing agglomeration is addedin between the steps.

In one aspect, a lower amount of rate-controlling agent enablesmanufacture of a tablet with a high drug load such as at least 35%, 40%,45%, 50%, 55%, or 60% dimethyl fumarate based on the total tabletweight.

In an embodiment of the invention step b) is performed in a fluid bedgranulator.

Another aspect of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) Dissolving (or suspending) a rate-controlling agent in the        form of a polymeric matrix material in water to obtain an        aqueous suspension thereof;    -   b) Spraying said aqueous suspension on granules of a fumaric        acid ester for a period of time sufficient to obtain a uniform        coating thereon;    -   c) Drying the granules obtained;    -   d) Optionally sieving or milling said granules;    -   e) Blending of any pharmaceutically acceptable excipients and        additives in a manner known per se to obtain a tablet        formulation;    -   f) Enteric coating and optionally film coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C. In an embodiment ofthe invention any of or all of the above steps are performed at atemperature to allow a product temperature not exceeding 40° C., such asnot exceeding 35° C., such as not exceeding 30° C. Thereby anysublimation of the active pharmaceutical ingredient is minimised orreduced and an energy-efficient process is obtained, mitigating loss ofAPI, thus reducing cost as well as improving environmental and workers'safety.

In an embodiment of the invention step b) is performed in a fluid bedgranulator.

Another embodiment of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) sieving and/or milling crystals of fumaric acid ester;    -   b) Blending of said crystals of fumaric acid ester, optionally a        rate-controlling agent in the form of a polymeric matrix        material, and any pharmaceutically acceptable excipients and        additives by direct compression to obtain a tablet formulation;    -   c) Enteric coating and optionally film coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C. In an embodiment ofthe invention any of or all of the above steps are performed at atemperature to allow a product temperature not exceeding 40° C., such asnot exceeding 35° C., such as not exceeding 30° C. Thereby anysublimation of the active pharmaceutical ingredient is minimised orreduced and an energy-efficient process is obtained, mitigating loss ofAPI, thus reducing cost as well as improving environmental and workers'safety.

Another embodiment of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) Blending of crystals of fumaric acid ester, optionally a        rate-controlling agent in the form of a polymeric matrix        material, and any pharmaceutically acceptable excipients and        additives;    -   b) milling the blended mix, add more additives and obtain by        direct compression the tablet formulation;    -   c) Enteric coating and optionally film coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C. In an embodiment ofthe invention any of or all of the above steps are performed at atemperature to allow a product temperature not exceeding 40° C., such asnot exceeding 35° C., such as not exceeding 30° C. Thereby anysublimation of the active pharmaceutical ingredient is minimised orreduced and an energy-efficient process is obtained, mitigating loss ofAPI, thus reducing cost as well as improving environmental and workers'safety.

Another embodiment of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) Optionally sieving or milling crystals of fumaric acid ester;    -   b) Blending said crystals of fumaric acid ester with any        pharmaceutically acceptable excipients and optionally a        rate-controlling agent in the form of a polymeric matrix        material in a manner known per se to obtain a tablet        formulation;    -   c) Roller compaction of this blend and sieving/milling thereof        in order to obtain granules;    -   d) Admixing of any further pharmaceutically acceptable        excipients to the granules to obtain a final mix ready for        tabletting;    -   e) Compression to tablets;    -   f) Enteric coating and optionally film coating of said tablets.

In an embodiment of the invention the fumaric acid ester is preblendedwith one or more pharmaceutically acceptable excipients before step a)above.

The stability of the formulations according to the invention may bedetermined by measuring the initial in vitro dissolution profile of thetablets and the in vitro dissolution profile after different periods ofstorage and comparing the in vitro dissolution profiles obtained. In anembodiment of the invention the tablets are stable for at least 6months, such as at least 9 months, such as at least 12 months, such asat least 18 months, such as at least 24 months, such as 36 months.

The stability of the formulations according to the invention may also bedetermined by standardized methods for measuring any changes in forexample assay, colour or degradation products.

In an embodiment of the invention, stability of a formulation can bedefined by objective criteria, such as e.g. a certain maximum change ofthe amount of API released at a predetermined time point during astandardized in vitro dissolution test, when comparing the initialtesting time point to testing at a later point in time. In an embodimentof the invention, the amount of the API released from the formulationstored under ICH conditions (such as degrees C./60% RH, such as 30degrees C./65% RH, such as 40 degrees C./75% RH) for a certain period oftime (such as at least 1 month, such as at least 3 months, such as atleast 6 months, such as at least 9 months, such as at least 12 months,such as at least 18 months, such as at least 24 months, such as at least36 months) c.f. the initial time point (time=0, set down of stabilitytesting)—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

1 hour after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

2 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

3 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

4 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

5 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed.

The pharmaceutical formulation according to the present invention is foruse for the treatment of psoriasis, including mild to moderate, moderateto severe, or severe plaque psoriasis.

It is to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims. Where a range of values is provided, it isunderstood that each intervening value, to the tenth of the unit of thelower limit unless the context clearly dictates otherwise, between theupper and lower limit of that range and any other stated or interveningvalue in that stated range is encompassed within the invention. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges and are encompassed within the invention,subject to any specifically excluded limit in the stated range. Wherethe stated range includes one or both of the limits, ranges excludingeither or both of those included limits are also included in theinvention. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Although anymethods and materials similar or equivalent to those described hereincan also be used in the practice or testing of the present invention,the preferred methods and materials are described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It must be noted that as used herein and in theappended claims, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

EXAMPLES

During the carrying out of all the following steps in the examplesnecessary precautions are taken (protective clothing with external airsupply, double gloves, arm covers, breathing mask, etc and/or containedequipment have to be used).

Example 1

1.2 kg dimethyl fumarate was sieved through a 700 μm sieve and placed inthe basket of a fluid bed granulator. 70.6 g polymer hydroxypropylcellulose HPC-SL was dissolved by stirring in 2753 g purified water andsprayed on the DMF over 2.5 to 3 hours. The granules were dried for 3minutes at 29° C. Several batches were blended and sieved through a 800μm sieve.

1730.7 g of the dried and additional through 500 μm sieved granules wereblended with 25 781.3 g granulated lactose (Tablettose 100), 66.7 gHPC-SL and a pre-blend of Aerosil® and Tablettose® with a barrel blenderat 20 rpm over 15 minutes. The pre-blend was prepared in a polyethylenebag of 4 g colloidal silicic acid (Aerosil®) and 390.6 g Tablettose® andsieved through 500 μm. Finally, 26.7 g magnesium stearate was added. Thefinal blend was pressed into biconvex tablets with a diameter of 8 mmand a weight of 225 mg.

Example 2

Film and enteric coating of core tablets according to example 1.

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared by adding 18 g Opadry to 102 g purified water. App. 66% of thissuspension was sprayed onto the core tablets over 20 minutes in a fluidbed chamber. The product temperature never exceeded 40° C. The coatingprocess was followed by a drying period of 9 minutes at 30° C. Theachieved coating was less than 0.7% weight increase compared to the coretablet weight.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 9.5 g triethyl citrate, 1.9 gglyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and stirring withthe UltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 gpurified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit® L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film-coated tablets in a fluid bed chamber. Thereal applied coating level was app. 2.2% weight increase compared to thecore tablet due to a high loss during the process.

Example 3

1.2 kg dimethyl fumarate was sieved through a 700 urn sieve and placedin the basket of a fluid bed granulator. 70.6 g hydroxypropyl celluloseHPC-SL was dissolved by stirring in 2753 g purified water and sprayed onthe DMF over 2.5 to 3 hours. The granules were dried for 3 minutes at29° C. and sieved through a 500 μm sieve.

964 g of the dried, sieved granules were blended with 565.5 g granulatedlactose (Tablettose® 100), 37.4 g HPC-SL and a pre-blend of Aerosil® andTablettose® with a barrel blender at 20 rpm over 15 minutes. Thepre-blend was prepared in a polyethylene bag of 2.3 g colloidal silicicacid (Aerosil®) and 282.7 g Tablettose® and sieved through 500 μm aswell. Finally, 14.9 g magnesium stearate was added. The final blend waspressed into 30 biconvex tablets with a diameter of 8 mm and a weight of250 mg.

Example 4

Film and enteric coating of core tablets according to example 3.

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry isprepared and applied as disclosed in example 2.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 9.5 g triethyl citrate, 1.9 gglyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and stirring withthe UltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 10g purified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit® L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film coated tablets in a fluid bed chamber at atemperature of 30° C. over app. 2.5 hours. A drying period at 30° C. for30 minutes and a 15 curing period at 35° C. for additional 30 minutesfollowed. The real applied coating level was app. 2.2% weight increasecompared to the core tablet due to a high loss during the process.

Example 5

1.2 kg dimethyl fumarate was sieved through a 700 μm sieve and placed inthe basket of a fluid bed granulator. 70.6 g hydroxypropyl celluloseHPC-SL was dissolved by stirring in 2753 g purified water and sprayed onthe DMF over 2.5 to 3 hours. The granules were dried for 3 minutes at29° C. Several batches were blended and sieved through 800 μm.

1416 g of the dried and additional through 500 μm sieved granules wereblended with 1002.9 g granulated lactose (Tablettose® 100), 54.6 gHPC-SL and a pre-blend of Aerosil® and Tablettose® with a barrel blenderat 20 rpm over 15 minutes. The pre-blend was prepared in a polyethylenebag of 3.3 g colloidal silicic acid (Aerosil®) and 501.4 g Tablettose®and sieved through 500 μm. Finally, 21.8 g magnesium stearate was added.The final blend was pressed into biconvex tablets with a diameter of 8mm and a weight of 275 mg.

Example 6

Film and enteric coating of core tablets according to example 5.

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared and applied as disclosed in example 2.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 9.5 g triethyl citrate, 1.9 gglyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and stirring withthe UltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 gpurified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit® L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film coated tablets in a fluid bed chamber at atemperature of 30° C. over app. 2.5 hours. A drying period at 30° C. for30 minutes and a curing period at 35° C. for additional 30 minutesfollowed. The real applied coating level was app. 2.2% weight increasecompared to the core tablet due to a high loss during the process.

Example 7

Film coating of core tablets according to example 2.

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared by adding 36 g Opadry to 204 g purified water. App. 66% of thissuspension was sprayed onto the core tablets over 35 minutes in a fluidbed chamber. The product temperature never exceeded 40° C. The coatingprocess was followed by a drying period of 16 minutes at 30° C. Theachieved coating was less than 2% weight increase compared to the coretablet weight.

Example 8

18 g of pure DMF (particle size 250-500 μm) were blended with 6.3 gHPC-SL, 9.1 g spray dried lactose (FlowLac® 100) and 0.045 g Aerosil.Finally, 0.3 g magnesium stearate was added and blended. The final blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 225 mg.

Example 9

The study was a single center study, following an open-label,randomized, crossover design to investigate the plasma concentrations,pharmacokinetics, safety and tolerability of pharmaceutical formulationsaccording to the invention c.f. the marketed formulation Fumaderm® asreference. The tablets were administered as a single oral dose of 240 mg(2 tablets containing 120 mg each) in each treatment period according torandomization to 20 healthy, male Caucasian subjects. The study wasdivided into four treatment periods (Treatment Period 1, 2, 3 and 4),which were separated by a wash-out phase of at least 7 days. Subjectswere screened for eligibility at least 21 to 2 days before firstadministration including: check of inclusion/exclusion criteria;demographic data (including age, body height, body weight, body massindex (BMI), and ethnic origin); physical examination; complete medicalhistory; 12-lead electrocardiogram (ECG); vital signs (blood pressure(BP), pulse rate (PR), and body temperature (BT)); clinical laboratoryparameters (hematology, 20 serum biochemistry, and urinalysis);documentation of concomitant illness and medication.

At each of the four treatment periods, subjects came to the Study Sitein the evening of Day 1 and remained there until the 24-hour bloodsample for PK analysis was drawn and all safety measurements wereperformed (=morning of Day 2).

The subjects fasted overnight. A single oral dose (of two tablets) ofone of the formulations according to the invention (Examples 2, 4 or 6),or two enteric-coated tablets of the reference medication Fumaderm® eachcontaining 120 mg dimethyl fumarate (total dose 240 mg dimethylfumarate) were administered on Day 1 (according to randomization).Administration was done to subjects who were in fasting conditiontogether with 240 ml tap water. Between each administration, a wash-outinterval of at least 7 days was maintained.

The following assessments/measurements were performed:

Blood sampling was performed for the determination of plasmaconcentrations and PK-parameters prior to, and at pre-scheduled timespost dosing.

Adverse events were documented in detail throughout the study.

Urine was collected prior to and at pre-scheduled times post dosing.

A follow-up examination was performed at least 7 days after the lastadministration (Treatment Period 4), including: physical examination;vital signs (BP, PR, and BT); body weight; 12-lead

ECG; clinical laboratory parameters (haematology, serum biochemistry,and urinalysis); documentation of concomitant medication and adverseevents.

Example 10 Preparation of Core Tablets

Dimethyl fumarate was sieved through a hand screen of 500 μm.

29.3 g of sieved dimethyl fumarate, 2.93 g of HPC-SL, 22.17 g ofgranulated lactose (Tablettose® 100), 0.07 g of Aerosil® as well as 0.49g of magnesium stearate were blended for 10 minutes. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of225 mg.

Example 11

Preparation of Core Tablets

Dimethyl fumarate was sieved through a hand screen of 500 μm.

500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of spray driedlactose (FlowLac® 100) and 1.2 g Aerosil® were blended with a barrelblender for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate wasadded and the mixture blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of250 mg.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solution sprayed onto the tablets was 2.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 1.8%.

Example 12 Preparation of Core Tablets

Dimethyl fumarate was sieved through a hand screen of 500 μm.

500 g sieved dimethyl fumarate, 48 g of HPC-SL and 447 g of granulatedlactose (Tablettose® 100) and 1.2 g Aerosil® were blended with a barrelblender for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate wasadded and the mixture blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of250 mg.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 99 g ofpurified water to 70-80° C., then 10.1 g of triethyl citrate, 2.0 g ofglyceryl monostearate (Cutina GMS V), and 0.8 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 198 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 224 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The solution was sprayed to a weight increase of the core tablets of 3%.

Example 13a Preparation of Core Tablets

Dimethyl fumarate was milled through 1143 um and 610 um screens.

500 g sieved dimethyl fumarate, 48 g of HPC-SL and 447 g of granulatedlactose (Tablettose® 100) and 1.2 g of Aerosil® were blended with abarrel blender for 15 minutes at 20 rpm. Finally, 4 g of magnesiumstearate was added and the mixture blended again for 10 min at 20 rpm.The blend was pressed into biconvex tablets with a diameter of 8 mm anda weight of 250 mg.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solids sprayed onto the tablets was 2.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 1.5%.

Example 13b

Preparation of core tablets was performed as described in Example 13a.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solids sprayed onto the tablets was 3.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 2%.

Example 14 Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g of Aerosil® was added. Theachieved particle size distribution was approx. 3%>500 μm, approx.65%>250 μm and approx. 6%<100 μm. The mean particle size was 290 μm.

The milled material was blended further with 240 g of HPC-SL and 2714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 275 mg. Thecore tablets may be enteric coated as described in example 16a or b.

Example 15 Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g of Aerosil® was added. Theachieved particle size distribution was approx. 3%>500 μm, approx.50%>250 μm and approx. 10%<100 μm. The mean particle size was 250 μm.

The milled material was blended further with 240 g of HPC-SL and 2714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 275 mg. Thecore tablets were optionally enteric coated as described in example 16b.

Example 16a Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 1193 g ofpurified water to 70-80° C., then 45 g of triethyl citrate, 13.5 g ofglyceryl monostearate (Cutina GMS V), and 5.4 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 2385 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 1500 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solids sprayed onto the tablets was 3.0% w/w resulting ina weight increase of the coated tablets compared to core tablets of2.5%.

Example 16b Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 1193 g ofpurified water to 70-80° C., then 45 g of triethyl citrate, 13.5 g ofglyceryl monostearate (Cutina GMS V), and 5.4 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 2385 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 1500 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solids sprayed onto the tablets was 3.5% resulting in aweight increase of the coated tablets compared to core tablets of 3%.

Example 17 Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g Aerosil® was added. Theachieved particle size distribution was 3%>500 μm, 63%>250 km and 6%<100km. The mean particle size was 290 μm.

The milled material was blended further with 240 g of HPC-SL and 2234 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 250 mg. Thecore tablets may be enteric coated as described in example 16a or b.

Example 18 Preparation of Core Tablets

2500 g of dimethyl fumarate is milled through 1575 um and 813 μmscreens. Before the second milling step 6 g of Aerosil® is added.

The milled material is blended further with 240 g of HPC-SL and 1714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate is added and themixture blended again for 10 min at 20 rpm. The blend is pressed intobiconvex tablets with a diameter of 8 mm and a weight of 225 mg. Thecore tablets may be enteric coated as described in example 16a or b.

Example 19

2.500 g of DMF is milled through 1575 μm and 813 μm screens. 240 g ofHPC-SL, 2.734 g of Tablettose 100 and 6 g of Aerosil is added andblended with the DMF. The blend is roller compacted and passed through a1 mm screen to obtain granules. 20 g of magnesium stearate is admixed toobtain a final mix ready for tabletting. Said mix is compressed totablets having a tablet weight of 275 mg. The core tablets may beenteric coated as described in example 16a or b.

Example 20

2.500 g of DMF is blended with 6 g of Aerosil and subsequently milledthrough 1575 μm and 813 μm screens. 240 g of HPC-SL and 2.734 g ofTablettose 100 is added and blended with the DMF and Aerosil. The blendis roller compacted and passed through a 1 mm screen to obtain granules.20 g of magnesium stearate is admixed to obtain a final mix ready fortabletting. Said mix is compressed to tablets having a tablet weight of275 mg. The core tablets may be enteric coated as described in example16a or b.

Example 21

A study as the one disclosed in example 25 was performed on tablets asdisclosed in examples 18 and 22 and compared with corresponding data forthe prior art formulation Fumaderm®. The results of the study are shownin Table I and Table II below.

TABLE I Coefficients of variation in % (CV). Example 2 Example 6Fumaderm ® AUC 22% 18% 38% Cmax 34% 26% 49%

TABLE II Summary Table: Percentage of subjects with adverse effects/sideeffects after administration of formulation according to examples 2 and6, respectively, compared to administration of Fumaderm ® Afteradministration of After administration of formulation acc. to ex 2formulation acc. to ex. 6 Adverse effect/ c.f. after administration c.f.after administration side effect of Fumaderm ® of Fumaderm ® Flushing35% 65% GI related 50% 73% adverse effects Any adverse 50% 77% effect

The above results of the clinical trial shows (Table II) that the testedformulations have a markedly reduced frequency of adverse effectscombined with a lower variability (cf. Table I) compared to Fumaderm®.This example thus shows that the erosion matrix tablets have a largereduction in variability in AUC and C_(max) vis-à-vis the prior artFumaderm® formulation.

Example 22 Preparation of Core Tablets

13.4 kg of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 32 g of Aerosil® was added. Theachieved particle size distribution was app. 3%>500 μm, approx. 52%>250μm and approx. 6%<100 μm. The mean particle size was 255 μm.

12.8 kg of the milled material was blended further with 1.2 kg of HPC-SLand 13.9 kg of granulated lactose (Tablettose® 100). Finally, 0.1 kg ofmagnesium stearate was added and the mixture blended again. The blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 275 mg. The core tablets were enteric coated as described below.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 7.2 kg ofpurified water to 70-80° C., then 138 g of triethyl citrate, 41 g ofglyceryl monostearate (Cutina GMS V), and 17 g of Tween 80 was added andstirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 8.9 kg of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 4.58 kg of Eudragit®L30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.After that the tables were cured over 2 hours at 40° C. The amount ofsolids sprayed onto the tablets corresponded to a 2.75% weight increaseresulting in a real weight increase of the coated tablets compared tocore tablets of app. 2.2%. Based on the shape of the tablet thiscorresponded to an enteric coat of 2.6 mg/cm².

Example 23 Preparation of Core Tablets

1136 g of dimethyl fumarate was blended with 2.73 g of Aerosil®, 109 gof HPC-SL and 1242.7 g of granulated lactose (Tablettose® 100). Thisblend was after that milled to a 613 μm screen. Finally, 9.1 g ofmagnesium stearate was added and the mixture blended again. The blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 275 mg. The core tablets were optionally enteric coated based on thedescription of the example before.

Example 24 Preparation of Core Tablets

14.7 kg of dimethyl fumarate was blended with 36 g of Aerosil® andde-agglomerated by milling through a 613 μm screens—app. 3%>500 μm,approx. 20%>250 μm and approx. 25%<100 μm. The mean particle size was165 μm.

13.7 kg of the milled material was blended further with 1.3 kg of HPC-SLand 14.9 kg of granulated lactose (Tablettose® 100). Finally, 0.11 kg ofmagnesium stearate was added and the mixture blended again. The blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 275 mg. The core tablets were enteric coated as described below.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 8.7 kg ofpurified water to 70-80° C., then 166 g of triethyl citrate, 49 g ofglyceryl monostearate (Cutina GMS V), and 20 g of Tween 80 was added andstirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 10.7 kg of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 5.5 kg of Eudragit®L30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.After that the tables were cured over 2 hours at 40° C. The amount ofsolids sprayed onto the tablets corresponded to a 2.75% weight increaseresulting in a real weight increase of the coated tablets compared tocore tablets of app. 2.4%. Based on the shape of the tablet thiscorresponded to an enteric coat of 2.9 mg/cm².

Example 25 Preparation of Core Tablets

13.3 kg of dimethyl fumarate was blended with 32 g of Aerosil® andde-agglomerated by milling through a 613 μm screens—app. 3%>500 μm,approx. 20%>250 μm and approx. 25%<100 μm. The mean particle size was165 μm.

12.53 kg of the milled material was blended further with 1.2 kg ofHPC-SL and 16.17 kg of granulated lactose (Tablettose® 100). Finally,0.10 kg of magnesium stearate was added and the mixture blended again.The blend was pressed into biconvex tablets with a diameter of 11.5 mmand a weight of 600 mg. The core tablets were enteric coated asdescribed below.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 8.7 kg ofpurified water to 70-80° C., then 166 g of triethyl citrate, 49 g ofglyceryl monostearate (Cutina GMS V), and 20 g of Tween 80 was added andstirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 10.7 kg of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 5.5 kg of Eudragit®L30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.After that the tables were cured over 2 hours at 40° C. The amount ofsolids sprayed onto the tablets corresponded to a 2.3% weight increaseresulting in a real weight increase of the coated tablets compared tocore tablets of app. 2%. Based on the shape of the tablet thiscorresponded to an enteric coat of 2.8 mg/cm².

Example 26

A unit dosage form consisting essentially of 375 mg±5%, 250 mg±5%, 187.5mg±5%, or 125 mg±5% dimethyl fumarate formulated as an entericallycoated erosion matrix tablet is prepared using the methods described in,for example, Examples 4, 6, 7, 10, 12, 13a, 13b, 16a, 16b, 20, and 24.In one embodiment, the 375 mg dose of dimethyl fumarate is administeredonce daily. In another embodiment, the 187.5% mg dose is administeredtwice daily. And in yet another embodiment, the 125 mg dose isadministered three times daily. Such low dosing regimens are especiallyadvantageous in reducing side effects associated with dimethyl fumaratetherapies.

1. A pharmaceutical composition for oral use in treating psoriasis,wherein said composition is in the form of an erosion matrix tabletcomprising a tablet core and one or more coating(s), wherein the tabletcore comprises i) 10 to 80% by weight dimethyl fumarate as an activesubstance, and ii) 1 to 50% by weight of one or more rate-controllingagents, wherein at least one of the one or more coating(s) is an entericcoating applied at a level of 1.5 to 3.5% by weight of the core, andwherein the dose of dimethyl fumarate to be administered is 375 mg±5%per day.
 2. The pharmaceutical composition according to claim 1, whereinthe dose to be administered is 375 mg per day.
 3. The pharmaceuticalcomposition according to claim 1 or 2, wherein the tablet core comprisesi) 30 to 60% by weight of dimethyl fumarate; and ii) 3 to 40% by weightof one or more rate-controlling agents.
 4. The pharmaceuticalcomposition according to claim 3, wherein the rate-controlling agent isa water-soluble polymer.
 5. The pharmaceutical composition according toany one of claims 1-4, wherein the rate-controlling agent is a cellulosepolymer or a cellulose derivative or a mixture thereof.
 6. Thepharmaceutical composition according to any one of the previous claims,wherein the rate-controlling agent is selected from the group comprisinghydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), methylcellulose, carboxymethyl cellulose and mixtures thereof.
 7. Thepharmaceutical composition according to claim 6, wherein therate-controlling agent is hydroxypropyl cellulose.
 8. The pharmaceuticalcomposition according to any one of the preceding claims, wherein thetablet core further comprises a binder.
 9. The pharmaceuticalcomposition according to claim 8, wherein the binder is lactose.
 10. Thepharmaceutical composition according to any one of the preceding claims,wherein the tablet core comprises: i) 35-55% by weight of dimethylfumarate; ii) 3-12% by weight of hydroxypropyl cellulose; and iii)40-60% by weight of lactose.
 11. The pharmaceutical compositionaccording to any one of the preceding claims, wherein the tablet corecomprises: 40-50% by weight of dimethyl fumarate; ii) 3-12% by weight ofhydroxypropyl cellulose; and iii) 45-55% by weight of lactose.
 12. Thepharmaceutical composition according to any one of the preceding claims,wherein the tablet core comprises: 42-48% by weight of dimethylfumarate; 3-10% by weight of hydroxypropyl cellulose; and iii) 45-52% byweight of lactose.
 13. The pharmaceutical composition according to claim11 or 12, wherein the amount of hydroxypropyl cellulose is 3-6% byweight.
 14. The pharmaceutical composition according to any one of thepreceding claims, wherein the tablet core further comprises 0.15-0.7% byweight of magnesium stearate and, optionally, 0.05 to 0.25% by weight ofsilicon dioxide.
 15. The pharmaceutical composition according to any oneof the preceding claims for administration once, twice or three timesdaily.
 16. The pharmaceutical composition according to any one of thepreceding claims for the treatment of mild to moderate, moderate tosevere, or severe plaque psoriasis.